Blood glucose variations and cardiovascular risk ... - medicalrecords.gr

Blood glucose variations and
cardiovascular risk in patients
with diabetes
Thessaloniki
13 November 2009
Oliver Schnell,
Executive Member of the Managing Board
Diabetes Research Institute,
Munich

UKPDS Follow-up:
Reduction of diabetes-related endpoints
and myocardial infarction
Holman R et al. New Engl J Med 2008;359, epub 10 September 2008

UKPDS Follow-up:
microvascular disease
and death from any cause
Holman R et al. New Engl J Med 2008;359, epub 10 September 2008

Multifactorial intervention in type 2 diabetes
The Steno 2 study
Composite endpoint
CV-death, MI or stroke, CABG or PCI, limb amputation or vascular surgery
(Gaede et al N Engl J Med 2008;358:580-91)
European guidelines: diabetes and cardiovascular disease

Severe hypoglycemic episodes in ACCORD, VADT, ADVANCE
ACCORD VADT ADVANCE
p

Probability of events of non-fatal myocardial infarction
with intensive glucose-lowering versus standard
treatment
Intensive treatment/
standard treatment
Participants Events
Weight of
study size
UKPDS 3071/1549 221/141 21.8%
PROactive 2605/2633 119/144 18.0%
ADVANCE 5571/5569 153/156 21.9%
VADT 892/899 64/78 9.4%
ACCORD 5128/5123 186/235 28.9%
Overall 17267/15773 743/754 100%
Lancet 2009;373:1765–72
Intensive treatment
better
Odds ratio
(95% CI)
0.6 0.8 1.0 1.2 1.4 1.6
Standard treatment
better
Odds ratio
(95% CI)
0.78 (0.62-0.98)
0.83 (0.64-1.06)
0.98 (0.78-1.23)
0.81 (0.58-1.15)
0.78 (0.64-0.93)
0.83 (0.75-0.93)

Probability of events of coronary heart disease with
intensive glucose-lowering versus standard treatment
Intensive treatment/
standard treatment
Participants Events
Weight of
study size
UKPDS 3071/1549 426/259 8.6%
PROactive * 2605/2633 164/202 20.2%
ADVANCE 5571/5569 310/337 36.5%
VADT 892/899 77/90 9.0%
ACCORD 5128/5123 205/248 25.7%
Overall 17267/15773 1182/1136 100%
*Included non-fatal myocardial infarction and death from all-cardiac mortality
Lancet 2009;373:1765–72
Intensive treatment
better
Odds ratio
(95% CI)
0.6 0.8 1.0 1.2 1.4 1.6
Standard treatment
better
Odds ratio
(95% CI)
0.75 (0.54-1.04)
0.81 (0.65-1.00)
0.92 (0.78-1.07)
0.85 (0.62-1.17)
0.82 (0.68-0.99)
0.85 (0.77-0.93)

HbA 1C (%)
SMBG testing is associated with better glycemic
control independent of diabetes type or therapy
9,0
8,5
8,0
7,5
7,0
8,7
All Comparisons P=.0001
7,7
8,8
8,2
Type 1 Type 2 +
Insulin
8,7
8,1
Type 2 +
OAD
*Compared any SMBG frequency with no SMBG.
8,1
7,7
Type 2 +
Lifestyle*
Less than defined frequency
At or above defined frequency
HbA 1C reductions:
Type 1: -1.0%
T2 + Insulin: -0.6%
T2 + OAD: -0.6%
T2 + Lifestyle: -0.4%
Karter AJ et al. Am J Med. 2001;111:1-9

• Self monitoring and glycemic control at Kaiser
Permanente
Northern California – an integrated health care system
• Longitudinal study of
• New user cohort (patients starting SMBG) – 16,091
• Ongoing user cohort (prevalent users) – 15,347

Karter A et al. (2006), Diabetes Care

ROSSO: Combined Non-fatal Endpoints
in diabetic patients with and without SMBG
% of patients with
non-fatal endpoint
10
8
6
4
2
0
186/1789
10.4%
p=0.002
107/1479
7.2%
no SMBG SMBG
Martin S et. al, Diabetologia 2006

ROSSO: Fatal Endpoints
in diabetic patients with and without
% of patients with
fatal endpoint
5
4
3
2
1
0
79/1725
4.6%
p=0.004
41/1543
2.7%
no SMBG SMBG
SMBG
Martin S et. al, Diabetologia 2006

Feedback of SMBG measurements to HCPs
important for maximising SMBG benefits
Reduction in HbA1c levels (%)
0
-0.6
-1.2
SMBG plus feedback reduced HbA 1c levels 0.6% more than
SMBG without feedback
SMBG vs.
Non-SM SMUG Non-SM SMUG SMBG
–0.4 –0.4
SMBG plus
feedback vs.
–1.0 –1.0
–0.6
is
No self-monitoring (non-SM)
SMUG (self-monitoring of urine
glucose)
SMBG
Jansen J. Curr Med Res Opin 2006;22:671–81.

HbA1c: Change from baseline
(DINAMIC 1 study)
Barnett AH et al 2008, Diabetes Obes Metab; 2008 10:1239-47

SMBG is a key component of
diabetes management programmes
“All persons with diabetes using insulin and/or oral
antidiabetes drugs can benefit from SMBG use”
American Association of Diabetes Educators 1
“SMBG empowers patients to take greater responsibility
for glycaemic control, improving self-awareness,
self-management and self-confidence”
American Diabetes Association 2
“SMBG should be available for all newly diagnosed people with
T2DM, as an integral part of self-management education”
International Diabetes Federation 3
1. AADE. The Diabetes Educator 2006;32(6):835–46.
2. ADA. Diabetes Care 1996;19(Suppl 1):S62–6.
3. IDF. http://www.idf.org/home/index.cfm?unode=B7462CCB-3A4C-472C-80E4-710074D74AD3

Postprandial
state
Postprandial state
Postabsorptive state
Fasting state
Breakfast Lunch Dinner 0.00am 4.00am Breakfast
Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11.

Relationship between postprandial blood
glucose peaks and CHD mortality
The evidence:
Honolulu
Heart Program
1987 8
Diabetes
Intervention Study
1996 7
Postprandial
hyperglycaemia
Rancho Bernardo
Study 1998 6
1. Nakagami T, et al. Diabetologia 2004;47:385–94.
2. DECODE. Diabetes Care 2003;26:688–96.
3. Shaw J, et al. Diabetologia 1999;42:1050–54.
4. Tominaga M, et al. Diabetes Care 1999;22;920–24.
5. Balkau B, et al. Diabetes Care 1998;21:360–67.
6. Barrett-Connor E, et al. Diabetes Care 1998;21:1236–39.
7. Hanefeld M, et al. Diabetologia 1996;39:1577–83.
8. Donahue R. Diabetes 1987;36:689–92.
DECODA
2004 1
DECODE
2001 2
Cardiovascular
mortality
Whitehall, Paris and
Helsinki Study 1998 5
Pacific and
Indian Ocean
1999 3
Funagata
Diabetes Study
1999 4
DECODA: Diabetes Epidemiology, Collaborative Analysis of Diagnostic Criteria in Asia
DECODE: Diabetes Epidemiology, Collaborative Analysis of Diagnostic Criteria in Europe

Multivariate hazard ratio
Postprandial hyperglycaemia is associated
with an increased risk of mortality
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
p=0.81
p=0.83
DECODA (n=6,817)
All-cause mortality CVD mortality

Plasma
Glucose
mg/dL
HbA1c is the same but glucose
300
200
100
0
profiles are very different
6 AM 10 AM 2 PM 6 PM 10 PM 2 AM
Time of Day
Monnier L: et al, JAMA (2006) 295: 1681-1687

Glucose Concentration
(mg/dL)
400
300
200
100
0
Variability of glucose
in type 1 diabetes
Mean A1C = 6.7%
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM

Variability of glucose:
A new independent risk factor for
hospital mortality in the ICU
Krinsley JS, Crit Care Med 2008; 36:3008-3013

Intermittent
apoptosis
vein
endothelial
Risso A, Mercuri F, Quagliaro
high glucose
in human umbilical
cells
enhances
in culture.
L, Damante G, Ceriello A.
Am J Physiol, 2001

Normal
STUDY DESIGN: DESIGN
glucose
High glucose
Alternating
(5mM)
(20mM)
glucose
(5/20mM)
14 days

50
Percentage of propidium
positive cells
40
30
20
10
0
Cell death of HUVECs cultured with
different concentrations of glucose
7 days
14 days
5 mmol/l glucose
20 mmol/l glucose
5/20 mmol/l glucose

A = normal glucose (5 mM)
B = high glucose (20mM)
C = alternating
low / high glucose (5/20 mM)

Flow-mediated dilation of
brachial artery (%)
Endothelial dysfunction and hyperglycemia
8
6
4
2
0
Flow-mediated dilation
of brachial artery (%)
NGT
IGT
DM
12
50
10
0
Fasting 1 hour 2 hours 8
6
4
2
0
–2
Fasting 1 hour 2 hours
0 100 200 300 400
Plasma glucose levels (mg/dl)
NGT = normal glucose tolerance; IGT = impaired glucose tolerance; DM = diabetes mellitus
Plasma glucose levels (mg/dl)
250
200
150
100
Kawano H et al. J Am Coll Cardiol 1999

Plasma TBARS level (nmol/ml)
3
2
1
Oxidative Endothelial stress dysfunction and postprandial induced by
hyperglycaemia hyerglycemia(II)
Fasting
1 hour
2 hours
NGT
IGT
DM
Kawano H et al. J Am Coll Cardiol 1999;34:146–54
Plasma TBARS level (nmol/ml)
4
3
2
1
0
0
100
200
300
Plasma glucose levels (mg/dl)
400

Oxidative Stress
and Glucose variability
MAGE = Mean Amplitude of Glycemic Excursions
Monnier, L, et al, JAMA, 295, 1681-1687, 2006

Traditional biomarkers of glycemia are
not associated with oxidative stress
HbA1C
Mean
Glucose
Post-meal
glucose
MAGE
8-Isoprostanes 0.06 0.22 0.55* 0.86*
*p

Glucose mmol/l
Increase in postprandial blood glucose preceeds
preprandial blood glucose elevation
Breakfast
preprandial postprandial
Morning
Duration
of diabetes
HbA1c: blue < 6,5 %, red 6,5 – 7 %, green 7,1 – 8 %, orange 8,1 – 9%,
brown 9,1 % and higher
Monnier L et al, Diabetes Care 2007 (30) 263-269

Contribution to HbA 1c (%)
Contribution of pre- and postprandial blood
glucose to HbA 1c
80
60
40
20
0
a,b
b
c
c
1 2 3 4 5
(10,2)
a: preand postprandial BG significantly different
b: significant os. other quintiles (ANOVA)
c: significant vs. quintile V (ANOVA)
a
a
Postprandial
blood glucose
Preprandial
blood glucose
Monnier et al. Diabetes Care 2003; 26: 881-885

Eur Heart J (2007) 28, 88-136
New ESC/EASD Guidelines
On hyperglycemia
Recommendation Class lass Level
GUIDELINES ON DIABETES, PRE-DIABETES
Information AND on post-load post CARDIOVASCULAR load glucose provides better DISEASES I A
information about future risk for CV disease than
fasting glucose, and elevated post-load post load glucose
also predicts increased CV risk in subjects with
normal fasting glucose
Improved control of post-prandial post prandial glycemia may lower CV risk and mortality
IIb C
The relationship between hyperglycemia and CV diseases should be seen as a continuum
I A

www.idf.org

www.idf.org

Consensus Statement
on Self-Monitoring of Blood Glucose
in Diabetes mellitus – a European
perspective
Schnell O, Alawi A, Battelino T, Ceriello A, Diem P, Felton A,
Grzeszczak W, Harno K, Kempler P, Satman I, Verges B.
Consensus Statement on Self-Monitoring of Blood Glucose in
Diabetes. Diabetes, Stoffwechsel und Herz (Diab Metabol
Heart) 2009; 18: 285-289

Consensus Statement
on SMBG: Intensified insulin treatment
4-8 tests every day
SMBG should be performed primarily preprandially
and at bedtime
Postprandial testing 7-10 times per week
Nocturnal testing once a week
Schnell O, Alawi A, Battelino T, Ceriello A, Diem P, Felton A, Grzeszczak W, Harno K,
Kempler P, Satman I, Verges B. European Consensus Statement on Self-Monitoring of
Blood Glucose in Diabetes. Diabetes, Stoffwechsel und Herz 2009; 18: 285-289

Consensus Statement on SMBG:
Conventional insulin treatment
2-4 tests every day
SMBG should be performed primarily preprandially
Postprandial testing 1-2 times per week
Nocturnal testing once a week or once every two
weeks
Schnell O, Alawi A, Battelino T, Ceriello A, Diem P, Felton A, Grzeszczak W, Harno K,
Kempler P, Satman I, Verges B. European Consensus Statement on Self-Monitoring of
Blood Glucose in Diabetes. Diabetes, Stoffwechsel und Herz 2009; 18: 285-289

Consensus Statement on SMBG:
Oral glucose-lowering treatment
6-8 tests per week with an equal amount of
preprandial and postprandial tests
In people who are not on insulin or do not test
frequently couplets (pre- and postprandial) are
recommended
Schnell O, Alawi A, Battelino T, Ceriello A, Diem P, Felton A, Grzeszczak W, Harno K,
Kempler P, Satman I, Verges B. European Consensus Statement on Self-Monitoring of
Blood Glucose in Diabetes. Diabetes, Stoffwechsel und Herz 2009; 18: 285-289

Self-monitoring
Individual
of blood
situations
glucose:
• Diabetic patients on oral glucose lowering agents:
- To provide informations on hypoglycemia
- To assess glucose excursions
- To assess medication and live style changes
- To monitor during intercurrent illness

SMBG values need to make a difference !
• meal and activity plans
• type and dose of oral agents
• regimen and dose of insulin
• interaction between physician and patient
• empowerment of the patient

Self-monitoring
in type
2 diabetes
of blood
glucose
mellitus: Summary
• Improvement of metabolic control reduces micro- and
macrovascular complications in diabetes
• Pre- and postprandial glucose and glycemic variability
matter, they can be visualized by SMBG
• SMBG is increasingly recommended in guidelines
(e.g. IDF, European Consensus), potential for more
elaborate recommendations
• Implementation at the national levels needs to be enforced
• SMBG needs to be individually tailored to the patient
• SMBG is a key element of an optimized diabetes
management

Consensus Report: Skills of caregivers needed
to interpret and act upon SMBG information
appropriately
• Interpret SMBG results relative to appropriate target
levels
• Possess the knowledge to make therapeutic adjustments
in therapy
• Create a simple action plan for the patient
• Adress fasting, postprandial, and post-meal excursion
glucose levels
• Act to prevent hypoglycemia

Consensus report: Skills of the patient in order
to appropriately perform, interpret and act upon
SMBG information
• Understand appropriate timing and testing sites for monitoring
• Interpret SMBG results relative to pretermined target levels
• Know how to modify diet, exercise, stress, and medication
dosing to modify level of glycemia
• Possess the knowledge to make therapeutic adjustments in
therapy
• Accurately record SMBG test results on paper or
electronically

Eur Heart J (2007) 28, 88-136
New ESC/EASD Guidelines
On hyperglycemia
Recommendation Class lass Level
GUIDELINES ON DIABETES, PRE-DIABETES
Information AND on post-load post CARDIOVASCULAR load glucose provides better DISEASES I A
information about future risk for CV disease than
fasting glucose, and elevated post-load post load glucose
also predicts increased CV risk in subjects with
normal fasting glucose
Improved control of post-prandial post prandial glycemia may lower CV risk and mortality
IIb C
The relationship between hyperglycemia and CV diseases should be seen as a continuum
I A

www.idf.org

• Agreement on patterns of SMBG
(e.g. pre- and postprandial BG),
individual recommendations for patients
• Emphasis on education
SMBG: Future directions
• Standardisation of display and communication of SMBG data
• Trials (RCT or observational) to reinforce that SMBG has
value in type 2 diabetes
– Clinical Outcomes, Glucose control (level and variability),
Hypoglycemia, QOL

www.idf.org

www.idf.org

HbA1c, %
12
10
8
6
DCCT
Ende End
HbA1c am Ende von DCCT
und während EDIC
Intensiv Konventionell
Intensive
p

Intensivierte Insulintherapie reduziert langfristig
das Auftreten kardiovaskulärer Komplikationen
bei Typ 1 Diabetes
Häufigkeit des ersten Auftretens
eines vordefinierten
kardiovaskulären Endpunkts
Häufigkeit des ersten Auftretens
eines nicht-tödlichen
Herzinfarkts, Schlaganfalls
oder Todes aufgrund einer
kardiovaskulären Erkrankung
DCCT/ EDIC Study Research Group
N Engl J Med 2005;353:2643-2653

Multifactorial intervention in type 2 diabetes
The Steno 2 study
Cumulative Incidence of All Cause Mortality
(Gaede et al N Engl J Med 2008;358:580-91)
1 57

ACCORD: Primary Endpoints
Subgroups
Evidence of benefit for
• Patients without preexisting cardiovascular events
• Patients with baseline HbA1c

• Three arm, open, parallel group randomized trial
• 435 patients with Dm and no insulin
• 3 groups: no SMBG, SMBG and no instructions,
SMBG and training to enhance motivation and
adherence to a healthy livestyle
• At 12 months no statistical differences differences in
HbA1c between the two groups
Farmer A et al, BMJ 2007; 335.132

• No statistical differences in HbA1c between
the groups
• 435 patients with Dm and no insulin
• 3 groups: no SMBG, SMBG and no advise,
SMBG and training to enhance motivation
and adherence to a healthy livestyle
Farmer A et al, BMJ 2007; 335.132

DIGEM: considerations
• The mean HbA1c ranged from 7.41 to 7.53 %:
this might have attenuated the need for a
modification or intensification of treatment
within any of the three groups
• The usage of oral antidiabetic agents (OADs) was
increased only in less than one third of the patients
(29 and 32% vs 30%)
• The difference in the number of SMBG
measurements per week was small between the
group with intensive SMBG vs. standard SMBG (7
times vs. 5 times)
Schnell O et al, J Diabetes Science Technology 2007; 1: 614-616

DIGEM - considerations
• The use of self-monitoring of glucose was somehow
blurred:
Nearly one third of the patients had performed self
monitoring of blood glucose prior to inclusion into the
study: 31.6 % in the control group
In the less and more intensive self monitoring groups:
26.7% and 32.5 %
Schnell O et al, J Diabetes Science Technology 2007; 1: 614-616

Recommended frequency and timing of
SMBG
It depends on the type of diabetes,
• the treatment approach and
• the educational level

Gestational Diabetes
High frequency testing: 4-8 tests per day or more
Postprandial testing 1-hour post-meal
Schnell O, Alawi A, Battelino T, Ceriello A, Diem P, Felton A, Grzeszczak W, Harno K,
Kempler P, Satman I, Verges B. European Consensus Statement on Self-Monitoring of
Blood Glucose in Diabetes. Diabetes, Stoffwechsel und Herz 2009; 18: 285-289

•
•
→
Recommended targets for Preprandial
< 6 mmol/l for
Children:
Blood Glucose
the
most
0-6 years: 5-8 mmol/l
→≥7 years: 4-8 mmol/l
→
→
Patients
Pregnant
with
patients
CAD: 5-7 mmol/l
women: 3,3-5 mmol/l
Schnell O, Alawi A, Battelino T, Ceriello A, Diem P, Felton A, Grzeszczak W, Harno K,
Kempler P, Satman I, Verges B. European Consensus Statement on Self-Monitoring of
Blood Glucose in Diabetes. Diabetes, Stoffwechsel und Herz 2009; 18: 285-289

•
•
→
→
Recommemded Target for
Postprandial Blood Glucose

Accu-Chek
360° View
Paper-Based –No software
or computer required
Simple Concept – Patient
tests 7 times per day over 3
day period; Record results on
easily-understood form
Comprehensive –Allows
recording of BG, meal size,
“feel-good” score
and more
Enhances Patient / HCP Interaction

INCA 2 Munich
Case reports

Postprandial
state
Postprandial state
Postabsorptive state
Fasting state
Breakfast Lunch Dinner 0.00am 4.00am Breakfast
Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11.

INCA: Intelligent Controll Assistent for
Diabetes

Smart assistant
Data transfer

Group 1:
INCA period
followed by control period
Group 2:
Control period
followed by INCA period
INCA : HbA1c
HbA1c Group 1
INCA period
HbA1c Group 2
INCA period